This invention relates to novel pharmaceutical formulations that are useful in particular in the oral administration of thyroid hormones.
The principal role of the thyroid gland is to regulate tissue metabolism through production of thyroid hormones. The main hormone produced is 3,5,3′,5′-tetraiodo-L-thyronine (L-thyroxine; T4) with smaller amounts of 3,5,3′-triiodo-L-thyronine (liothyronine; T3) also being produced. The hormones are produced utilising dietary iodine, which is absorbed from the gastrointestinal tract as iodide and transported into the thyroid gland.
Whilst T4 enters the circulation only by way of direct glandular secretion, very little T3 is secreted by the thyroid gland, with most extra-glandular T3 being produced by deiodination of circulating T4. The metabolic activity of T3 is about 3 to 5 times higher than T4 and it has been postulated that T3 is the active hormone, with T4 acting largely as a pro-drug.
Synthetically-produced T3 and T4 are employed in the treatment of hypothyroidism. The low endogenous production of thyroid hormone gives rise to symptoms associated with a slow metabolism, such as fatigue (including muscle fatigue), weight gain and/or increased difficulty losing weight, coarse/dry hair and/or hair loss, dry/rough/pale skin, cold temperature intolerance, muscle cramps and/or frequent muscle aches, constipation, depression, irritability, memory loss, abnormal menstrual cycles and decreased libido.
This extremely common condition may result from inflammatory diseases of the thyroid, such as autoimmune thyroiditis, or as a side effect following certain medical treatments.
When given as a replacement therapy in the treatment of hypothyroidism, the optimum effects of T4 may not be achieved for several weeks and there is a slow response to changing dosage.
T3, on the other hand, is administered to achieve a more rapid effect and/or a shorter duration of action. It is typically administered in the form of the sodium salt at an initial adult dose of 5 to 25 μg daily, increased gradually to a maintenance dose of 60 to 75 μg (although up to 100 μg may be required in some patients).
High concentrations of circulating T3 resulting from oral administration of conventional T3-containing immediate release tablet formulations (which provide for the equivalent of between 5 and 50 μg of T3) are associated with side effects, particularly in patients with angina or ischemic heart disease, or where infarction or dysrhythmia may prove fatal.
Congestive heart failure exhibits high mortality and increasing prevalence. The use of T3 in the treatment of this condition has been described. However, in order to be safe and effective in such treatment, the circulating concentration of T3 must remain within a narrow and specific therapeutic window. A sustained release oral dosage form is required to facilitate this.
Sustained release or extended release oral dosage forms, which are used to control (i.e. slow) the rate at which an orally administered drug compound is absorbed into the systemic circulation, are widely described in the scientific and patent literature (see, for example, Venkatraman et al, Handbook of Pharmaceutical Controlled Release Technology, Wise (Ed.), Marcel Dekker, New York, 2000, pp. 435-445; Qiu and Zhang, ibid., pp. 465-503; Charman and Charman, Modified-Release Drug Delivery Technology, Rathbone et al (Eds.), Marcel Dekker, New York, 2003, pp. 1-10).
Two consequences of slowing the rate of absorption are: (a) a reduction in the peak blood level of drug (Cmax) relative to the same dose of drug administered by way of an immediate release dosage form; and (b) an extended duration of circulation of drug in the systemic circulation. The latter may result in a potential reduction in dosing frequency.
Basic approaches for producing sustained release dosage forms include matrix systems, which typically comprise drug encapsulated in insoluble, slowly eroding and/or swelling materials (often polymers); reservoir systems, including polymer coated tablets, pellets or granules; ion-exchange systems; and osmotic systems.
In order to function optimally, many of these approaches rely on the drug that is employed having a reasonable solubility in aqueous media. Providing a sustained release dosage form for use with poorly-soluble drug compounds presents more of a challenge and, accordingly, formulation options for use with such drugs are more limited (see Qiu and Zhang above).
Recent innovations in drug discovery, such as combinatorial chemistry and high-throughput screening, have resulted in more efficient and effective means of drug-lead generation and the optimisation of new drug-lead molecules (see, for example, Remington, The Science and Practice of Pharmacy, 20th Edition, Chapter 28, Lippincott Williams & Wilkins (Ed.), Philadelphia, 2000). However, although highly potent compounds have frequently been identified using these technologies, such compounds have often been found to exhibit extremely low aqueous solubility.